It is well established that lipases and esterases serve an important role in digestion or absorption of dietary lipids, degradation or accumulation of lipids in the living body, detoxication or degradation of hazardous compounds, etc. Among others, a hormone-sensitive lipase (hereinafter abbreviated as HSL), expression of which is widely found in tissues including adipose tissues, such as testis, heart, skeletal muscle, pancreas, aorta, etc., has been attracting the attention as a regulatory factor of fat deposits in vivo and energy consumption, glucose metabolism or arteriosclerosis lesion formation (Holm, C. and Osterlund, T. Methods in Molecular Biology, 109, 109–121).
That is, reportedly, HSL as a rate-limiting enzyme for neutral fats (especially triglycerides) in the respective tissues, not only controls the amount of fatty acids supplied, which are utilized for energy production in muscle tissues or brown adipocytes (Himms-Hagen, J. Prog. Lipid Res., 28, 67–115 (1989)) or for ligand production of nuclear receptors or PPARs (Tontonoz, P. et al., Cell, 79, 1147–1156 (1994)) but is also associated with regulation of insulin secretion in pancreatic β cells (Mulder, H. et al., Diabetes, 48, 228–232 (1999)). It has also been suggested that HSL is likely to be associated with the formation of atherosclerosis nest and its retraction as neutral cholesteryl ester hydrolase (hereinafter abbreviated as NCEH) responsible for degradation of intracellular cholesteryl ester (Escarry, J-L et al., Arterioscler. Thromb. Vasc. Biol., 18, 991–998).
However, there is no difference in body weight between HSL-deficient mice prepared by Osuga et al. and wild type mice. Moreover, the hormone-sensitive triglyceride degradation activity in adipocytes or the NCEH activity in macrophages significantly remains in the HSL-deficient mice, while no change is observed in body temperature generation under cold conditions (Osuga, J. et al., Proc. Natl. Acad. Sci. USA, 97, 787–792 (2000)). It is thus strongly suggested that another HSL-like lipase or esterase would participate in various lipolysis processes hitherto considered to be associated with HSL, and such a lipase or esterase is engaged in fatty acid production in adipocytes or muscle tissues or foam cell formation in macrophages, with expectation that the lipase or esterase is likely to play an important role in the development of arteriosclerosis, hyperlipidemia, mellitus diabetes, obesity, etc.
So far it is known that enzymes, which has been reported to express neutral lipid degradation enzymes in adipose tissues, aorta or macrophages, include a bile salt activation lipase (Li, F. and Hui, D. Y., J. Biol. Chem., 272, 28666–18671 (1997)), a lipoprotein lipase (Mattsson, L. et al., J. Clin. Invest., 92, 1759–1765 (1993)), monocyte/macrophage serine esterase I (Zschunke, F. et al., Blood, 78, 506–512 (1991)), an endothelium-derived lipase (Jaye, M. et al., Nature Genet., 21, 424–428 (1999)), a lysosome acidic lipase (Sakurada, T. et al., Biochim. Biophys. Acta, 424, 204–212 (1976)), etc. However, it makes no sense at all that any of these enzymes would be replaceable for the functions of HSL in view of localization in tissues/cells, substrate specificity, optimum pH for the activities, presence or absence of hormone sensitivity, activity variation patterns during the course of foam cell formation of macrophages, etc. It has thus been desired to isolate a novel lipase or esterase derived from adipocytes or macrophages.
The present invention provides novel proteins having an esterase activity, in particular, a triglyceride degradation activity, etc., partial peptides or salts thereof, DNAs encoding the proteins, recombinant vectors, transformants, methods of manufacturing the proteins, drugs comprising the proteins or DNAs, antibodies to the proteins, screening methods/screening kits for compounds having the activity of promoting the esterase activity of the proteins, compounds obtained by the screening methods, pharmaceuticals comprising the compounds above, etc.